Clinical effect of different concentrations of ropivacaine in the labor analgesia of dural puncture epidural technique for obese puerperae.

BACKGROUND: This study was performed to analyze the clinical effect of different concentrations of ropivacaine in the labor analgesia of the dural puncture epidural (DPE) technique for obese puerperae. METHODS: One hundred and fifty first-term obese women who received vaginal delivery and required labor analgesia in our hospital were selected prospectively for this study, and divided into groups A, B, and C. The three groups of puerpera were given epidurals with different concentrations of ropivacaine (0.075%, 0.10%, and 0.125%) with sufentanil (0.5 µg/ml) for the labor analgesia regimen. The visual analog scale (VAS), Ramsay scale, and Bromage scale of puerperae before analgesia and at different time points after anesthesia, and analgesic onset time, analgesia time, first PCEA time, PCEA pressing time, ropivacaine consumption, labor time, maternal blood pressure and heart rate, maternal adverse reactions, blood gas analysis in the neonatal umbilical artery, and Apgar score were observed. RESULTS: The analgesia onset time, PCEA pressing time, and ropivacaine consumption in group C were lower and the analgesia time and the first PCEA time were longer than those in groups A and B. At T1-T3 and T5, VAS scores of group A were higher than those in groups B and C, Ramsay score of group A was lower than that of groups B and C at T2-T3, and Bromage score of group C at any time point was higher than other two groups. The time of the second stage of labor in groups B and C was longer than that in group A, which in group C was longer than that in group B. Compared with groups A and C, the blood pressure and heart rate of puerperae in group B were closer to normal values. Three different concentrations of ropivacaine had no significant effect on the umbilical artery blood gas analysis indices and Apgar scores at 1st minute and 5th minute in neonates. The incidence of maternal adverse reactions in group C was lower than those in groups A and B. CONCLUSION: 0.1% ropivacaine combined with 0.5 µg/ml sufentanil through DPE technique has good analgesic efficacy and few adverse effects in obese puerperae.

Periprostatic Adipose Tissue: A New Perspective for Diagnosing and Treating Prostate Cancer.

Prostate cancer (PCa) is the most common tumor of the male genitourinary system. It will eventually progress to fatal metastatic castration-resistant prostate cancer, for which treatment options are limited. Adipose tissues are distributed in various parts of the body. They have different morphological structures and functional characteristics and are associated with the development of various tumors. Periprostatic adipose tissue (PPAT) is the closest white visceral adipose tissue to the prostate and is part of the PCa tumor microenvironment. Studies have shown that PPAT is involved in PCa development, progression, invasion, and metastasis through the secretion of multiple active molecules. Factors such as obesity, diet, exercise, and organochlorine pesticides can affect the development of PCa indirectly or directly through PPAT. Based on the mechanism of PPAT's involvement in regulating PCa, this review summarized various diagnostic and therapeutic approaches for PCa with potential applications to assess the progression of patients' disease and improve clinical outcomes.

Glycopolymer-Based Antiswelling, Conductive, and Underwater Adhesive Hydrogels for Flexible Strain Sensor Application.

With the fast development of soft electronics, underwater adhesion has become a highly desired feature for various sensing uses. Currently, most adhesive hydrogels are based on catechol-based structures, such as polydopamine, pyrogallol, and tannic acid, with very limited structural variety. Herein, a new type of glycopolymer-based underwater adhesive hydrogel has been prepared straightforwardly by random copolymerization of acrylic acid, acetyl-protected/unprotected glucose, and methacrylic anhydride in dimethyl sulfoxide (DMSO). By employing a DMSO-water solvent exchange strategy, the underwater adhesion was skillfully induced by the synergetic effects of hydrophobic aggregation and hydrogen bonding, leading to excellent adhesion behaviors on various surfaces, including pig skins, glasses, plastics, and metals, even after 5 days of storage in water. In addition, the underwater adhesive hydrogels with simple and low-cost protected/unprotected carbohydrate compositions showed good mechanical and rheological properties, together with cytocompatibility and antiswelling behavior in water, all of which are beneficial for underwater adhesions. In application as a flexible strain sensor, the adhesive hydrogel exhibited stable and reliable sensing ability for monitoring human motion in real time, suggesting great potential for intelligent equipment design.

Bupi Yishen formula may prevent kidney fibrosis by modulating fatty acid metabolism in renal tubules.

BACKGROUND: Bupi Yishen formula (BYF), a traditional Chinese herbal mixture, has demonstrated better effectiveness than Losartan in preserving renal function and preventing composite severe adverse outcomes in patients with advanced chronic kidney disease (CKD) in a recent randomized controlled trial. Prior studies have shown that BYF exerts anti-inflammatory and anti-fibrotic effects in the kidneys of CKD models, but the underlying mechanisms have not been fully elucidated. PURPOSE: The aim of this study was to investigate the protective effects of BYF administration on profibrotic phenotypic changes in the kidney and to elucidate its fundamental mechanisms of action. METHODS: Adenine and 5/6 nephrectomy rat models were administered with two doses of BYF extract (15 or 30 g/kg/d) by intragastric administration, and Losartan treatment was used as a positive control group. The relationship between BYF renoprotection and restoration of fatty acid dysregulation was examined using the two fibrosis models and TGFb1-induced human tubular HK2 cells. Transcriptomic profiles of the fibrotic kidneys obtained from adenine-induced CKD rats were used to identify the key mechanisms that are affected by BYF intervention. Human relevance and clinical implications were established by re-analysis of the microarray databases of CKD patients and immunostaining on human biopsy specimens. RESULTS: BYF effectively prevented kidney histological damage and ameliorated renal malfunction in the adenine rat model of CKD. BYF robustly attenuated the significant increase in profibrotic and proapoptotic markers in fibrotic kidneys of adenine-induced CKD rats. Transcriptomic analyses of the fibrotic kidneys of the adenine rats identified fatty acid metabolism as the key dysregulated pathway affected by BYF prevention. BYF significantly reversed defective fatty acid oxidation (FAO) and the intracellular lipids accumulation in the fibrotic kidneys induced by 5/6 nephrectomy. Furthermore, BYF prevented dysfunctional fatty acid metabolism, which were associated with the significant improvement of TGFb1-induced profibrotic changes in HK2 human proximal tubular cells. Furthermore, analyses of kidney microarray databases and biopsy specimens of CKD patients suggested that FAO defect is common in CKD in humans. CONCLUSION: Our exploratory study found that BYF may exert protective effects on renal fibrosis by regulating the fatty acid metabolism of renal tubular cells, which may be a key mechanism for preventing kidney fibrosis in CKD.

Key events in cancer: Dysregulation of SREBPs.

Lipid metabolism reprogramming is an important hallmark of tumor progression. Cancer cells require high levels of lipid synthesis and uptake not only to support their continued replication, invasion, metastasis, and survival but also to participate in the formation of biological membranes and signaling molecules. Sterol regulatory element binding proteins (SREBPs) are core transcription factors that control lipid metabolism and the expression of important genes for lipid synthesis and uptake. A growing number of studies have shown that SREBPs are significantly upregulated in human cancers and serve as intermediaries providing a mechanistic link between lipid metabolism reprogramming and malignancy. Different subcellular localizations, including endoplasmic reticulum, Golgi, and nucleus, play an indispensable role in regulating the cleavage maturation and activity of SREBPs. In this review, we focus on the relationship between aberrant regulation of SREBPs activity in three organelles and tumor progression. Because blocking the regulation of lipid synthesis by SREBPs has gradually become an important part of tumor therapy, this review also summarizes and analyzes several current mainstream strategies.

Single-pulse characterization of the focal spot size of X-ray free-electron lasers using coherent diffraction imaging.

The characterization of X-ray focal spots is of great significance for the diagnosis and performance optimization of focusing systems. X-ray free-electron lasers (XFELs) are the latest generation of X-ray sources with ultrahigh brilliance, ultrashort pulse duration and nearly full transverse coherence. Because each XFEL pulse is unique and has an ultrahigh peak intensity, it is difficult to characterize its focal spot size individually with full power. Herein, a method for characterizing the spot size at the focus position is proposed based on coherent diffraction imaging. A numerical simulation was conducted to verify the feasibility of the proposed method. The focal spot size of the Coherent Scattering and Imaging endstation at the Shanghai Soft X-ray Free Electron Laser Facility was characterized using the method. The full width at half-maxima of the focal spot intensity and spot size in the horizontal and vertical directions were calculated to be 2.10 ± 0.24 µm and 2.00 ± 0.20 µm, respectively. An ablation imprint on the silicon frame was used to validate the results of the proposed method.

Structurally Dynamic Gelatin-Based Hydrogels with Self-Healing, Shape Memory, and Cytocompatible Properties for 4D Printing.

Three-dimensional (3D) printable hydrogels with a shape memory effect have emerged as a new class of 4D printing materials recently and found wide applications in various fields. However, synergistically endowing such materials with good mechanical strength and biocompatibility for biomedical uses remains challenging. In this study, a series of multiresponsive hydrogels have been prepared through a dynamic covalent imine/Diels-Alder network from biocompatible starting materials of modified gelatin and poly(ethylene glycol)-based polymers. By further secondary crosslinking with a hyperbranched triethoxysilane reagent (HPASi) that contains multiple supramolecular hydrogen bonding, the hydrogels presented a strengthened self-healing and temperature-responsive shape memory effect. With the additional features of superior stretchability (elongation at break up to 523%), good cytocompatibility, and 3D printable properties, these multifunctional hydrogels showed great potential for broad biomedical applications.

Circular Patterns of Dynamic Covalent Hydrogels with Gradient Stiffness for Screening of the Stem Cell Microenvironment.

As extracellular matrix (ECM) mimetic materials, hydrogels have been widely used for broad biomedical applications. However, with so many physical or chemical cues in the matrix that regulate cell behaviors or functions, it remains challenging to design a customizable hydrogel with the desired properties on demand. In the current study, we aim to establish a circular-patterned hydrogel model with gradient stiffness for screening the most favorable ECM environment for specific cells or certain application purposes. First, six types of hydrogels with a wide stiffness range of 1.2-28.9 kPa were prepared by dynamic covalent cross-linking between gelatin derivatives and oxidized hyaluronic acid. Taking advantage of their instantaneous self-healing property from dynamic chemistry, the hydrogels were further spliced into one whole piece of circular-patterned hydrogel. When rabbit bone marrow mesenchymal stem cells were seeded in the center, the influences of matrix stiffness on the regulation of stem cell adhesion, migration, and differentiation were directly observed and compared under one visual field. In addition, these hydrogels all possessed good biocompatibility, degradability, and injectability, showing great potential for tissue-engineering-related applications.

Metagenomics-based systematic analysis reveals that gut microbiota Gd-IgA1-associated enzymes may play a key role in IgA nephropathy.

Background: IgA nephropathy (IgAN) is the most common type of glomerulonephritis in Asia. Its pathogenesis involves higher expression of galactose-deficient IgA1 (Gd-IgA1) and dysregulated intestinal mucosal immunity. The objective of this study was to explore whether specific gut microbiota and associated enzymes affect Gd-IgA1 in IgAN. Methods: This study carried out shotgun metagenomic sequencing with Illumina on fecal samples collected from 20 IgAN patients (IgAN group) and 20 healthy controls (HCs group) who were recruited from January 2016 to December 2018 at the Second Clinical College of Guangzhou University of Chinese Medicine. Differences analysis in gut microbiota was performed to determine the overall microbiota composition, the representative enterotypes, and the microbiota abundance. Correlations between gut microbiota and clinical indicators were assessed by Spearman's analysis. Moreover, the functional prediction of microbial communities and the quantitative calculation of enzymes encoded by microbiome were performed using the MetaCyc pathway and the bioBakery three platform, respectively. Results: Bacteroides plebeius and Bacteroides vulgatus levels were higher, while Prevotella copri and Alistipes putredinis levels were lower in the IgAN group compared to HCs group. Enterotype I characterized by Bacteroides was closely related to the IgAN patients. Moreover, Bacteroides fragilis, Flavonifractor plautii and Ruminococcus gnavus were characteristic bacteria enriched in IgAN patients. Spearman's correlation analysis found that Eggerthella lenta and Ruminococcus bromii were positively correlated with urine protein-creatinine ratio, while Ruminococcus gnavus showed a direct association with red blood cells in urine, and Bacteroides vulgatus and Ruminococcus gnavus were positively correlated with eGFR. These results indicated that intestinal dysbacteriosis occurred in IgAN patients and was associated with clinical and biochemical features. In addition, MetaCyc pathway analysis predicted microbiota-related metabolic pathways, including the biosynthesis of amino acids and glycans, were associated with the IgAN group. Microbial enzymes analysis highlighted that Gd-IgA1-associated α-galactosidase and α-N-acetyl-galactosaminidase secreted by Flavonifractor plautii were enriched in IgAN patients. Conclusion: These findings suggested that α-galactosidase and α-N-acetyl-galactosaminidase secreted by Flavonifractor plautii might be related to the production of Gd-IgA1, indicating that enzymes originated from abnormal intestinal microbiota may contribute to the production of Gd-IgA1 and play an important role in the pathogenesis of IgAN.

A Bibliometric and Visualized Analysis of Uremic Cardiomyopathy From 1990 to 2021.

Background: Uremic cardiomyopathy is commonly presented in chronic kidney disease (CKD), and it severely affects the prognosis of patients with CKD. In the past few decades, the investigation of uremic cardiomyopathy has developed rapidly. However, no report has summarized the situation of uremic cardiomyopathy research to date. This study aimed to evaluate the state of uremic cardiomyopathy research in the last 30 years and identify important topics and achievements, as well as emerging trends through bibliometric analysis. Materials and Methods: Publications related to uremic cardiomyopathy were collected from Science Citation Index Expanded. HistCite, VOSviewer, CiteSpace, and the Bibliometrix Package were used for bibliometric analysis and visualization, including the analysis of the overall distribution of the annual publication, leading countries, and active institutions and authors, core journals, co-cited references, and keywords. Results: A total of 2,403 studies related to uremic cardiomyopathy were obtained, and progress related to uremic cardiomyopathy was slower in past 3 years. A total of 10,077 authors from 2,697 institutions in 89 countries or regions reported investigations on uremic cardiomyopathy. The United States of America was the most productive and the most cited country. Myles Wolf, Joseph I Shapiro, and Carmine Zoccali published most articles in uremic cardiomyopathy, and journals in nephrology possessed core status in the field. Phosphate metabolism was the hotspot in uremic cardiomyopathy research in recent years, and future progress may concentrate on phosphate metabolism, endogenous natriuretic factors, and novel biomarkers. Conclusion: The United States of America and European countries played central roles in uremic cardiomyopathy research, while Chinese scholars should be more involved in this field. Global publications on uremic cardiomyopathy have entered platform stage, and the fibroblast growth factor-23-klotho axis remained a hotspot in this field. Endogenous natriuretic factors and novel biomarkers may be potential directions in future investigations.

Nanosecond protonic programmable resistors for analog deep learning.

Nanoscale ionic programmable resistors for analog deep learning are 1000 times smaller than biological cells, but it is not yet clear how much faster they can be relative to neurons and synapses. Scaling analyses of ionic transport and charge-transfer reaction rates point to operation in the nonlinear regime, where extreme electric fields are present within the solid electrolyte and its interfaces. In this work, we generated silicon-compatible nanoscale protonic programmable resistors with highly desirable characteristics under extreme electric fields. This operation regime enabled controlled shuttling and intercalation of protons in nanoseconds at room temperature in an energy-efficient manner. The devices showed symmetric, linear, and reversible modulation characteristics with many conductance states covering a 20× dynamic range. Thus, the space-time-energy performance of the all-solid-state artificial synapses can greatly exceed that of their biological counterparts.

Protective effects of the Bupi Yishen formula on renal fibrosis through PI3K/AKT signaling inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: The Bupi Yishen Formula (BYF) is a patented Chinese herbal compound that has been long used to treat chronic kidney disease (CKD) in the clinic. However, its main active ingredients and underlying mechanisms remain to be elucidated. AIM: Identify the major active ingredients of BYF and investigate its protective effects and specific molecular mechanisms in renal fibrosis. METHODS: First, we performed network pharmacology analysis combined with molecular docking to predict the main active compounds, potential therapeutic targets, and intervention pathways that might exert the anti-fibrotic effect of BYF in the kidney. Then, we validated the predictions in both adenine-induced CKD rats and TGFß1-induced HK-2 cells. RESULTS: A total of 233 common targets, 25 core targets, and 10 main active compounds from BYF were selected by network pharmacology analyses. Then, GO and KEGG functional enrichment analyses indicated that the renoprotection conferred by BYF against renal fibrosis was mainly associated with the PI3K/AKT signaling. Besides, the molecular docking showed that the 10 main active compounds of BYF were closely docked with three main PI3K/AKT pathway proteins. During the experimental validations, BYF improved renal impairment and alleviated fibrosis by inhibiting the PI3K/AKT signaling activity in the kidney of adenine-induced CKD model rats. Moreover, increased PI3K/AKT signaling activation was associated with fibrotic phenotype changes in adenine-induced CKD rats and TGFß1-induced HK-2 cells. On the other hand, BYF treatment reduced PI3K/AKT signaling activation and decreased renal fibrogenesis in a dose-dependent manner, thereby indicating that PI3K/AKT signaling was essential for BYF to exert its anti-fibrotic effects. Finally, the inhibitory effect of BYF on renal fibrogenesis was not enhanced while blocking the PI3K/AKT pathway with a broad spectrum PI3K inhibitor (LY294002). CONCLUSION: In the present study, we applied a comprehensive strategy based on systemic pharmacology to reveal the anti-fibrotic mechanisms of BYF, at least partially, through the inhibition of PI3K/AKT signaling activation. We also identified BYF as a potential therapeutic agent for renal fibrosis and CKD progression.

Current apparent treatment-resistant hypertension in patients undergoing peritoneal dialysis: A multi-center cross-sectional study.

Apparent treatment-resistant hypertension (aTRH) is the most commonly used term to report resistant hypertension (RH) and is considered as a common problem in dialysis population. However, few reports have focused on peritoneal dialysis (PD) hypertensive patients. The authors conducted a multi-center cross-sectional study involving 1789 PD patients from nine centers in Guangdong, China. The prevalence of aTRH was estimated by home blood pressure (BP) monitoring. Evaluating drug adherence through Eight-item Morisky Medication Adherence Scale (MMAS-8) and pill counting was performed to assess RH in one PD center. Related factors of aTRH were analyzed using logistic regression analysis. The prevalence of aTRH in PD patients was estimated at 42.2% (755 out of 1789 hypertensive patients) based on home BP. Of those, 91.4% patients were classified as uncontrolled RH, 2.0% as controlled RH, and 6.6% as refractory hypertension. The prevalence of RH was 40.6% and 41.9% among those with medium/high adherence based on the MMAS-8 scores and the pill counting rate, respectively. PD patients who were younger, with higher body mass index, with lower serum albumin and poorer dialysis adequacy were significantly associated with higher aTRH incident. In conclusion, the present study demonstrates a high prevalence of aTRH in PD population, which occurs in about two in five treated hypertensive patients. Nutritional status and dialysis adequacy might tightly associate with aTRH.

Propensity-matched comparison of mortality between peritoneal dialysis and hemodialysis in patients with type 2 diabetes.

BACKGROUND: The optimal choice of dialysis modality for diabetic patients remains controversial. This study aimed to compare mortality between peritoneal dialysis (PD) and hemodialysis (HD) in end-stage renal disease (ESRD) patients with type 2 diabetes (T2D). METHODS: Our observational, longitudinal cohort consisted of all incident ESRD patients with T2D who received either PD or HD in our center from January 2012 to December 2017 and were followed until December 2019. Propensity scores were used to select a 1:1 matched cohort. Mortality was compared between dialysis modalities using Kaplan-Meier survival analysis, and risk factors for mortality were estimated using multivariate Cox regression analyses. RESULTS: The median follow-up times were 35.5 months in the PD group (n = 134) and 41.6 months in the HD group (n = 134, p = 0.0381). The 1-, 2-, 3-, 5-, and 7-year patient survival rates were 98%, 91%, 77%, 61%, and 35% for diabetic PD patients and 96%, 88%, 81%, 60%, and 57% for diabetic HD patients. Kaplan-Meier survival analysis showed that overall mortality did not significantly differ between modalities (log-rank = 0.9473, p = 0.6575). Using a multivariate Cox regression model, advanced age and increased cholesterol at the initiation of PD treatment were independent risk factors associated with mortality, whereas under HD therapy, the risk factors associated with mortality were lower BMI and higher HbA1c. CONCLUSIONS: These results suggest that in patients with T2D, mortality is comparable between PD and HD irrespective of whether there are the first 2 years or over the 2-year period, and that different mortality predictor patterns exist between patients treated with PD versus HD.

The "Half-Perc" technique using a simple modified metal trocar for peritoneal dialysis catheter placement: results of a 3-year follow-up of 280 patients and a literature review.

PURPOSE: There is an ongoing debate about the ideal technique for peritoneal dialysis (PD) catheter insertion in patients with end-stage renal disease (ESRD). A half-percutaneous ("Half-Perc") technique shares some of the advantages of both percutaneous technique and traditional open surgery. This retrospective study aimed to evaluate the clinical feasibility, safety, and effects of the "Half-Perc" technique for PD catheter placement, and to compare the clinical outcomes of the "Half-Perc" technique with various imaging-assisted percutaneous techniques from the current literature. METHODS: We included 280 consecutive patients with ESRD who underwent the "Half-Perc" insertion of the first PD catheter between September 2016 and September 2019. We recorded baseline characteristics, operative parameters, catheter-related complications, catheter survival, and the reason behind PD cessation. RESULTS: We included 174 men and 106 women, with a mean age of 50.4 years (range, 11-85 years). The mean operative time was 28.8 min (range, 15-38 min) and technical success rate was observed in 278 patients (99.3%). There were 28 episodes (10%) of mechanical complications with initial catheters occurring during the follow-up. Catheter malfunctions were the most common mechanical complication and were observed in 15 patients. Peritonitis was the most frequent catheter-related complication, with 32 episodes of peritonitis observed in 29 (10.4%) patients. After a mean follow-up period of 15.4 months (range, 2-36 months), 235 patients (83.9%) survived with their initial PD catheter by the end of the study. Of the 280 patients analyzed, 35 patients (12.5%) ceased PD at some stage during follow-up. The most common reason for PD cessation was kidney transplantation (18 patients (6.4%)), followed by death (9 patients (3.2%)) and switch to hemodialysis (HD) (7 patients (2.5%)), and recovery of renal failure (1 patient (0.4%)). CONCLUSION: The "Half-Perc" technique, including a modified metal trocar, is a simple, safe, and effective method for PD catheter placement that can be used for patients with ESRD.

Characteristics Analysis, Clinical Outcome and Risk Factors for Fungal Peritonitis in Peritoneal Dialysis Patients: A 10-Year Case-Control Study.

Background: Fungal peritonitis (FP) is a rare but severe complication that can appear in patients receiving peritoneal dialysis (PD). This study aimed to investigate the incidence rate and clinical characteristics of FP, evaluate clinical outcomes between FP and bacterial peritonitis (BP) patients on PD, and especially estimate the risk factors for FP outbreak. Methods: All episodes of FP diagnosed in our hospital from January 1, 2011, to December 31, 2020, were reviewed in this single-center study. FP cases were analyzed and compared with patients diagnosed with BP in a 1:6 ratio matching for case-control study. Patient information, including clinical information, biochemical analysis, and outcomes, was recorded. Univariate and multivariate logistic regression model were used to analyze the risk factors for FP. Results: A total of 15 FP episodes were observed in 15 PD patients, with an FP rate of 0.0071 episodes per patient-year. Seventeen strains of fungi were isolated and identified. Candida was the most common pathogen (15 strains, 88.2%), followed by Aspergillus fumigatus (2 strains, 11.8%). Between the groups, FP group showed a higher rate of HD transfer and catheter removal, and a lower rate of PD resumption in the short-term outcome (all P < 0.01), while no significant difference in the mortality was noted during the whole study period. The multivariate logistic regression analysis showed that longer PD duration (odds ratio [OR] 1.042, 95% confidence interval [CI] 1.012-1.073, P < 0.01), higher serum potassium (OR 3.373, 95% CI 1.068-10.649, P < 0.05), elevated estimated glomerular filtration rate (eGFR) (OR 1.845, 95% CI 1.151-2.955, P < 0.05), reduced serum albumin level (OR 0.820, 95% CI 0.695-0.968, P < 0.05) and peritoneal effluent polymorphonuclear (PMN) count (OR 0.940, 95%CI 0.900-0.981, P < 0.01) were significantly increased the risk for FP. Conclusion: These results suggested that FP leads to higher rate of catheter removal and HD transfer, and a lower rate of PD resumption than BP, and that additional attention should be paid to hypoalbuminemia, increased serum potassium, long PD duration, and low peritoneal effluent PMN in PD patients.

Uncovering Bupi Yishen Formula Pharmacological Mechanisms Against Chronic Kidney Disease by Network Pharmacology and Experimental Validation.

Chronic kidney disease (CKD) is a leading public health problem with high morbidity and mortality, but the therapies remain limited. Bupi Yishen Formula (BYF) - a patent traditional Chinese medicine (TCM) formula - has been proved to be effective for CKD treatment in a high-quality clinical trial. However, BYF's underlying mechanism is unclear. Thus, we aimed to reveal BYF pharmacological mechanism against CKD by network pharmacology and experimental studies. Network pharmacology-based analysis of the drug-compound-target interaction was used to predict the potential pharmacological mechanism and biological basis of BYF. We performed a comprehensive study by detecting the expression levels of fibrotic and inflammatory markers and main molecules of candidate signal pathway in adenine-induced CKD rats and TGF-ß1-induced HK-2 cells with the treatment of BYF by western blotting and RT-qPCR analyses. Using small interfering RNA, we assessed the effect of BYF on the TLR4-mediated NF-κB mechanism for CKD renal fibrosis and inflammation. Network pharmacology analysis results identified 369 common targets from BYF and CKD. Based on these common targets, the BYF intervention pathway was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. We found that Toll-like receptor (TLR) and NF-κB signaling pathways were enriched. Then, we demonstrated that BYF significantly improved the adenine-induced CKD rat model condition by kidney dysfunction improvement and reversing renal fibrosis and inflammation. Subsequently, we investigated BYF's effect on the TLR4/NF-κB signaling pathway. We found that TLR4 and phospho-NF-κB (p-p65 and p-IKßα) expression was significantly upregulated in adenine-induced CKD rats, then partially downregulated by BYF. Furthermore, BYF inhibited fibrotic and inflammatory responses, as well as TLR4, p-p65, and p-IKßα in TGF-ß1-induced HK-2 cells. Additionally, the BYF inhibitory effect on fibrosis and inflammation, and NF-κB pathway activation were significantly reduced in TGF-ß1-induced HK-2 cells transfected with TLR4 siRNA. Altogether, these findings demonstrated that the suppression of TLR4-mediated NF-κB signaling was an important anti-fibrotic and anti-inflammatory mechanism for BYF against CKD. It also provided a molecular basis for new CKD treatment drug candidates.

Strong, Self-Healing Gelatin Hydrogels Cross-Linked by Double Dynamic Covalent Chemistry.

Hydrogels constructed from natural sources have received increased attention recently, including applications in biomedical fields. They are protein or polysaccharide cross-linked scaffolds that display water retention and are able to recognize host cargos. Their excellent biocompatibility does not always combine with high mechanical strength (up to 136 kPa) and thermostability, making them less useful in biomedical applications. This paper reports biocompatible gelatin hydrogels, double cross-linked via imine and Diels-Alder (DA) dynamic covalent frameworks. They showed integrated advantages of adjustable and durable mechanical strength, good thermal stability, biocompatibility for promoting cell growth and reasonable degradable rate. These hydrogels possess remarkable self-healing property, acid/alkali resistance at 65 °C and good integrity in organic solvents at 130 °C, holding great potential for biomedical applications in the areas such as cartilage regeneration, articular reconstruction or soft robotics.

A longitudinal study of cardiac structure and function using echocardiography in patients undergoing peritoneal dialysis.

BACKGROUND: Peritoneal dialysis (PD) can be associated with abnormal cardiac structure and function and increased mortality risk. Therefore, in this study, we analyzed the cardiac structure and function dynamic changes using echocardiography during the first 2 years of PD therapy. We also assessed its associations with all-cause mortality risk after 2 years of follow-up. METHODS: End-stage renal disease (ESRD) patients that have started PD from 2011 to 2017, and had echocardiography at baseline and years 1 and 2, were included in this study. Echocardiographic parameters were compared between baseline and year 2. Multivariable Cox models were used to estimate the association between echocardiographic parameters changes and all-cause mortality risk. RESULTS: We finally enrolled 72 PD patients in this study. The mean right ventricular diameter (RVD) increased from baseline (18.31 mm) to year 1 (18.75 mm) and year 2 (19.65 mm). We also observed a significant decrease in cardiac output (CO) between baseline and year 2. Additionally, a slight decrease trend in ejection fraction (EF) was observed. Finally, every 1 % increase in RVD was associated with a 68.2 % higher mortality risk after dialysis (HR, 1.682; 95 % CI, 1.017-2.783). CONCLUSIONS: Our results demonstrated a susceptibility for deteriorated right cardiac structure and function during the first 2 years of PD treatment. Also, higher all-cause mortality risk was observed after 2 years of PD. Altogether, these results highlighted the need for additional focus on regular echocardiographic examinations during long-term PD management. TRIAL REGISTRATION: The PD-CRISC cohort, registered with the Chinese Clinical Trial Registry ( ChiCTR1900023565 ).

Generation and Characterization of Mouse Models of C3 Glomerulonephritis With CFI D288G and P467S Mutations.

C3 glomerulopathy (C3GP) is a disease entity caused by abnormality of the complement alternative pathway (AP) and characterized by C3 deposition in glomeruli. Many variations or mutations of complement factors are believed to underlie the susceptibility to C3GP, but there is a lack of experimental evidence. We have recently reported a patient with C3 glomerulonephritis (C3GN) and compound heterozygosity of two novel variations in the complement factor (CFI). Here, we generated a mouse model to mimic the CFI variations for studying pathogenicity of CFI variations in C3GN development. We used the CRISPR/Cas9 system to make mutant mouse lines that carried D288G and P467S mutations in CFI, respectively, and crossed them to generate mice with compound heterozygosity of CFI D288G and P467S. The mice were all normal in either SPF (specific pathogen free) or regular environment. When treated with lipopolysaccharides (LPS), a bacterial endotoxin that mimics infection and sepsis, the mice developed albuminuria, kidney function impairment, and C3 glomerular deposition at levels comparable with the wild-type mice. The mice with other genotypes concerning CFI D288G and P467S were also tested in parallel. Unexpectedly, we found that the D288G homozygotes all developed severe mesangial deposition of C3 in the LPS model, indicating that CFI D288G variation was involved in the C3 deposition, a key feature of C3GN. The mouse lines generated in the present study can be used to further study the role of CFI variations in C3GN development; in addition, they may be used to screen and test infections and environmental factors capable of triggering C3GN.